Chemotalk Newsletter

Chemotalk Newsletter, Vol. 113 September 1, 2017

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By Dave Levitan

    A phase III trial failed to demonstrate superiority of eribulin over treatment of physician¹s choice (TPC) in patients with heavily pretreated NON-SMALL-CELL LUNG CANCER (NSCLC). The agent did have activity in this setting, but did not improve outcomes over other options.

    "Despite the availability of second-line therapies, including pemetrexed, erlotinib, and docetaxel, clinical evidence of third-line or later treatment options still remains limited," wrote study authors led by Nobuyuki Katakami, MD, PhD, of the Institute of Biomedical Research and Innovation Hospital in Kobe, Japan.

    Eribulin is a microtubule dynamics inhibitor, and earlier research had suggested it may be effective in NSCLC. The new trial was a randomized, open-label, phase III study including 540 patients who had received at least two prior therapies, including a platinum-based doublet and an EGFR tyrosine kinase inhibitor. They were randomized to receive either eribulin (270 patients) or TPC (270 patients). Results of the study were published in Annals of Oncology.

    In the TPC cohort, 27% received vinorelbine, 32% received gemcitabine, 24% received docetaxel, and 17% received pemetrexed. Most patients had received at least three prior treatment regimens; patient characteristics were well balanced between the groups.

    The median overall survival was 9.5 months for both the eribulin and the TPC groups, for a hazard ratio (HR) of 1.16 (95% CI, 0.95­1.41; P = .13).
The median progression-free survival was also similar, at 3.0 months with eribulin and 2.8 months with TPC, for an HR of 1.09 (95% CI, 0.90­1.32; P = .39).

    The objective response rate was 12% with eribulin, and 15% with TPC; 51% of eribulin patients had stable disease, compared with 43% of those in the TPC group. The clinical benefit rate and disease control rate were also no different between the study arms, and quality-of-life measures were also similar.

    Serious adverse events were seen in 36% of eribulin patients and in 32% of TPC patients. Grade 3 or higher asthenia occurred more frequently in the eribulin group (8.2% vs 2.6%). One treatment-related death occurred with eribulin (cardiac failure).

    "Our results are in contrast to those of previous phase III trials with eribulin in patients with METASTATIC BREAST CANCER or advanced LIPOSARCOMA or LEIOMYSARCOMA, in which a significant improvement in overall survival with eribulin vs comparator was observed," the authors wrote. Still, the agent has shown activity in the third-line setting, with a manageable safety profile, they concluded.

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By Leah Lawrence

    Mortality from COLORECTAL CANCER (CRC) has decreased since 1970 in young black patients aged 20 to 54, but has increased in white patients since 1995 in those aged 30 to 39 years and since 2005 in those aged 40 to 54 years after decades of decreasing, according to a research letter published in JAMA.

    Rebecca L. Siegel, MPH, of the American Cancer Society in Atlanta, Georgia, and colleagues, wrote that these "disparate racial patterns conflict with trends in major CRC risk factors like obesity, which are similar in white and black individuals," and that the "increased mortality is particularly unexpected among those aged 50 to 54 years, for whom screening has been recommended since the 1970s."

    The researchers obtained CRC mortality rates per 100,000 population from 1970 to 2014 from the SEER Stat database. Data obtained was for individuals aged 20 to 54 years and mortality data was from causes reported on death certificates.

    From 1970 to 2014, 242,637 people died from CRC. Median age at death was 49 years. Overall, CRC mortality rates declined in those aged 20 to 54 from
6.3 per 100,000 in 1970 to 3.9 per 100,000 in 2004. However, rates then increased by 1% annually to 4.3 per 100,000 in 2014.

    Data revealed that this increase in mortality occurred only in white individuals, where mortality rates increased by 1.4% annually from 3.6 per 100,000 in 2004 to 4.1 per 100,000 in 2014. Conversely, black individuals saw decreases in mortality rates from 8.1 per 100,000 in 1970 to 6.1 per
100,000 in 2014.

    Throughout the entire study period, black individuals had decreasing mortality rates among those aged 20 to 49; since 1993, mortality rates also decreased among those aged 50 to 54. In contrast, mortality rates increased for white individuals aged 30 to 39 from 1995 to 2014 and for those aged 40 to 49 and 50 to 54 from 2005 to 2014.

    "This study is limited by its ecologic nature and inaccuracies in about 5% of all death certificates listing CRC as the underlying cause of death," the researchers wrote. "Escalating mortality rates in young and middle-aged adults highlight the need for earlier CRC detection through age-appropriate screening and more timely follow-up of symptoms."

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By Dave Levitan

    Olaparib tablet maintenance therapy provided a significant improvement in progression-free survival (PFS) over placebo in patients with relapsed, platinum-sensitive OVARIAN CANCER with a BRCA1/2 mutation, according to a new phase III trial. Toxicity was generally manageable with the therapy.

    Though advanced ovarian cancer patients often respond well to first-line chemotherapy, subsequent lines of therapy after recurrence have less and less beneficial effect. "A substantial unmet need exists for well tolerated therapies that can improve long-term disease control in patients with recurrent ovarian cancer," wrote study authors led by Eric Pujade-Lauraine, MD, PhD, of Université Paris Descartes in France.

    The PARP inhibitor olaparib has shown promise in phase II all-comer studies of relapsed ovarian cancer. The new study aimed to confirm this in a phase III setting of relapsed ovarian cancer with BRCA1 or BRCA2 mutations.
It included 295 patients, randomized to either olaparib (196 patients) or placebo (99 patients); all had received at least two lines of previous chemotherapy. The study was published online ahead of print in Lancet Oncology.

    After a median follow-up of approximately 22 months, the investigator-assessed PFS was 19.1 months with olaparib and 5.5 months with placebo, for a hazard ratio (HR) of 0.30 (95% CI, 0.22­0.41; P < .0001). The 12-month PFS rate was 65% with the study drug, and 21% with placebo. At 24 months, these rates were 43% and 15%, respectively.

    The median time to first subsequent therapy was 27.9 months with olaparib and 7.1 months with placebo. The median time to progression was not reached in the olaparib group, while it was 18.4 months in the placebo group. Overall survival data was not yet mature, but as of this analysis there was no difference between the groups, with an HR of 0.80 (95% CI, 0.50­1.31; P = .43).

    Measures of quality of life, based on the FACT-O assessment, were no different between olaparib and placebo.

    The overall incidence of grade 3­5 adverse events (AEs) in the study was low. The most common grade 3 or worse AE with olaparib was anemia (18% grade 3, 1% grade 4, vs 2% and 0% with placebo). Serious AEs were seen in 18% of olaparib and 8% of placebo patients.

    "The improvement in PFS seen using the olaparib tablet formulation in this disease setting is compelling because patients were able to maintain a good quality of life while experiencing a delay in disease progression and, therefore, a delay until the symptoms associated with subsequent chemotherapy treatments," the authors wrote.

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By Leah Lawrence

    Patients with newly diagnosed MULTIPLE MYELOMA treated with lenalidomide maintenance therapy after undergoing autologous stem-cell transplantation
(ASCT) had significantly improved overall survival compared with observation or placebo, according to the results of a meta-analysis published in the Journal of Clinical Oncology.

    Data for the analysis were taken from three clinical trials‹Cancer and Leukemia Group B 100104, Gruppo Italiano Malattie Ematologiche dell¹Adulto RV-MM-PI-209, and Intergroupe Francophone du Myelome 2005-02‹all of which showed a progression-free survival benefit with maintenance lenalidomide.
However, none of the trials were powered to detect a difference in overall survival.

    "This study demonstrates a statistically significant and clinically meaningful improvement in overall survival with lenalidomide maintenance," wrote Philip L. McCarthy, MD, Roswell Park Cancer Institute in Buffalo, New York, and colleagues. "With new, highly active, triplet induction regimens enhancing depth and duration of response as well as ongoing studies evaluating the optimal timing of ASCT, the use of lenalidomide maintenance for transplantation-eligible patients can be considered a standard of care."

    The meta-analysis included patient-level data from the three randomized clinical trials on 1,208 patients (605 treated with maintenance therapy).
Median progression-free survival was twice as long in patients assigned to lenalidomide maintenance compared with observation or placebo (52.8 months vs 23.5 months; hazard ratio [HR], 0.48; 95% CI, 0.41­0.55). The improvement in progression-free survival was consistent in all three studies.

    At a median follow-up of 79.5 months, 64% of patients assigned lenalidomide and 54% of patients assigned to placebo or observation were alive. The median overall survival had not yet been reached for patients assigned to lenalidomide therapy compared with 86 months for placebo or observation (HR, 0.75; 95% CI, 0.63­0.90; P = .001).

    "The heterogeneity analysis demonstrated that all three studies contributed to the positive results of the meta-analysis," the researchers noted. "The HRs for each study are consistent with an overall survival improvement with lenalidomide maintenance vs placebo or observation."

    Patients assigned to lenalidomide had a higher cumulative incidence rate of second primary malignancy prior to disease progression compared with placebo or observation; however, they had a lower cumulative incidence rate of progression, death, or death as a result of myeloma. In addition, patients assigned lenalidomide had significantly longer time to progressive disease or second-line therapy compared with placebo or observation (HR, 0.51; 95% CI, 0.45­0.59; P < .001).

    "The costs of maintenance therapy should be weighed against the costs of shorter survival, earlier progression, and earlier use of subsequent lines of therapies for patients without maintenance," the researchers wrote.

"Understanding the role of minimal residual disease detection and immune reconstitution after ASCT, as well as developing early endpoints as surrogates for long-term outcomes, should allow us to develop clinical strategies to further improve overall survival."

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NEXT ISSUE: October 1, 2017


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Elaine Jesmer

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